Risk Of Lower Limb Amputation Research Articles

MESENCHYMAL STEM CELLS (MSCS) AS A THERAPY FOR CHRONIC WOUND HEALING IN DIABETIC FOOT ULCERS: A REVIEW ARTICLE

Diabetic foot ulcer is a chronic and frequent complication in diabetic patients. Foot ulcers occur in 15-25% of people with diabetes, and most of them require amputation. Conventional treatments for DFU have not been effective enough to reduce the amputation rates. Thus, an effective method to accelerate the healing of diabetic foot ulcers is required. Recently, stem cells have emerged as a promising adjuvant therapy. One of the numerous types of stem cells used in chronic wound healing therapy is Mesenchymal Stem Cells (MSCs). MSCs may be associated with shorter wound healing time, rapid tissue regeneration, and reduced risk of lower limb amputation through all mechanisms. This article summarizes and critically reviews the published literature on the use of MSCs to enhance chronic wound healing in DFUs.

Higher Prevalence of Cancer in Patients with Diabetic Foot Syndrome.

Background: Diabetes mellitus (DM) is associated with a higher prevalence of many forms of cancer. Diabetic foot syndrome (DFS) is associated with higher risk of lower limb amputation and mortality not all explainable with a cardiovascular profile at greater risk compared with DM patients without DFS. DFS could be associated with an increasing cancer incidence. To explore a possible link between DFS and cancer, comparing two cohorts of patients (DFS+ and DFS-) with a cohort of superimposable non-DM controls. Methods: We retrospectively analysed the databases of our department for all consecutive patients admitted between January 2019 and December 2021, selecting all DM pts, and sorting DFS+ pts, admitted for foot complications, from DFS- ones, admitted for other reasons. Cases of pancreatic cancer as well as cancer-related admissions were excluded. Patients were compared to non-DM patients admitted for non-oncological medical problems. The primary endpoint was to compare the prevalence of cancer among the groups, while the secondary endpoint was to look for predictors for cancer in the groups studied. Results: A cohort of 445 consecutive DM inpatients (222 DFS+ and 223 DFS-) and 255 controls were studied. Cancer prevalence in DFS+ group was significantly higher than in DFS- (p = 0.008) and controls (p = 0.031), while no differences were observed between DFS- and the controls. Univariate regression analysis showed a significant association between cancer and DFS (p = 0.007), age at admission (p ≤ 0.001), years of diabetes (p = 0.017) and haemoglobin concentration [Hb] (p = 0.030). In the multivariate regression analysis with DFS, age at admission and [Hb], only DFS (p = 0.021) and age at admission (p ≤ 0.001) persisted as independent factors associated with cancer. Conclusions: A higher prevalence of cancer in DFS+ patients than in DFS- patients and non-diabetic controls is reported. DFS and age can both be considered independent predictors of cancer in patients with DM.

Effect of Sensory Re-Education with Aerobic Training on Sensation and Balance among Diabetic Peripheral Neuropathy Patients: A Pilot Study

Background: People with diabetes have 10 to 30 times higher risk of lower limb amputation than people without thedisease. 85% of non-traumatic amputations in diabetic patients begin with a foot ulcer. Therefore, early interventionis necessary to control the symptoms of diabetic peripheral neuropathy and improve balance. Resistance andaerobic training reduce diabetic symptoms by lowering HbA1C levels. In order to restore functional sensibility,improve adaptive functioning, and improve balance, sensory re-education and aerobics are combined. Therefore,the aim of this study is to find out the effect of Sensory re-education and aerobics on sensation and balance amongdiabetic peripheral neuropathy patients.Purpose: The Purpose of the study is to determine the effects of sensory re-education with aerobic training onsensory perception and balance in Diabetic peripheral neuropathy patients.Material and Method: This study included diabetic individuals of both genders between the ages of 45-60, lowPAR-Q risk scores and Toronto clinical neuropathy scores (TCNS) between 6 and 11. A total of 20 participantswere randomly selected and received sensory re-education with aerobics for six weeks.Results: Individuals with diabetic peripheral neuropathy experienced statistically significant improvement inTCNS from 9.3±1.25 to 4.5± 1.3, in BBS 48.5 ± 2.70 to 41.7±1.41, in TUG 8.12±1.28 to 6.95 ±1.30, with a P value of <0.01.Conclusion: Sensory re-education with aerobic training for 6 weeks of duration reported improvement in sensoryperception and balance among people with diabetic peripheral neuropathy patients.

Perceptions of primary and secondary care clinicians treating diabetic foot: A pan India study and quantitative analysis

AimThe study quantifies clinicians' perceptions and challenges during different stages of diabetic foot treatment. Diabetic neuropathy (DN), which is a major consequence of diabetes, significantly increases the risk of lower limb amputation. This can be prevented to a large extent by foot care, early detection, and lesion treatment. MethodsNinety-two Indian clinicians of various demographics, medical specializations, and experiences were interviewed. Diabetic foot treatment by primary and secondary care clinicians was assessed. This study evaluates aspects related to patient awareness, compliance, and shortcomings of current diagnostic techniques. ResultsA two-sample Mann-Whitney statistical method was used to infer the perceptions of clinicians on hypothesis questions. Primary and secondary care clinicians' perceptions differed for the hypotheses related to objective assessment (p-value = 0.001), operator variability (p-value = 0.03), and patient compliance (p-value = 0.047). Conversely, both groups held comparative perspectives for the awareness (p-value = 0.369) and examination time (p-value = 0.276) hypotheses. ConclusionsAll clinicians strongly supported the need for an objective assessment to reduce the misdiagnosis of DN. Further, DNis often underdiagnosed due to a lack of awareness and knowledgeamong people with diabetes. Secondary care clinicians acknowledged a need for trained operators to reduce reliability errors. These insights provide directions for future research in this field.

Minor amputation after revascularization in chronic limb-threatening ischemia: What is the optimal timing?

Patients with chronic limb-threatening ischemia (CLTI) have a high risk of lower limb amputation and loss of walking independence. Minor amputations play a key role in ensuring walking independence and they represent a challenge in terms of timing and level for vascular surgeons. A major cause of re-amputation is a defect in wound healing and a possible predictor of re-amputation for non-healing wounds could be the incorrect timing of minor amputation after revascularization. The lack of evidence in the literature leads to a wide variability of choices in clinical practice. The purpose of this study was to try to find the optimal timing analysing the risk of re-amputation in CLTI patients who have undergone successful revascularization and minor amputation focussing on timing of minor amputation. We conducted a single centre retrospective analysis on a cohort of 151 patients consecutively admitted to our hospital for CLTI (Rutherford 5) between January 2014 and April 2022. All the enrolled patients underwent successful revascularization of lower limbs and a minor amputation for dry acral necrosis. The characteristics of the patients and the revascularization procedures were collected and analysed. Patients were divided into two groups based on the timing of minor amputation performed before (group 1) or after the day (group 2) that best predicts the risk of re-amputation according to a Receiver Operating Characteristic (ROC) curve analysis. The primary outcome of this study was the risk of re-amputation during the first 60days of follow-up after a primary minor amputation, with revascularization still effective. The impact of the timing of minor amputation after revascularization, the type of revascularization and the presence of risk factors known to prolong the wound healing process were evaluated in a uni- and multi-variable logistic regression model. Systemic hypertension, and type of revascularization (i.e. open vs endovascular) were independent predictors of the risk of re-amputation at 60days (HR 4.26, 95% CI 1.30-14.04, p = .017 and HR 2.35, 95% CI 1.16-4.78, p = .018, respectively). Moreover, time ≤14days between revascularization and first amputation was associate with a clear, albeit not statistically significant, trend toward increased risk of re-amputation (HR 2.09, 95% CI 0.97-4.51, p = .06). In a cohort of patients who underwent a successful revascularization for CLTI and a minor amputation for dry gangrene in the first 14 days after revascularization, a higher -although not significant-risk of re-amputation was reported. In this cohort of patients, a delayed demolitive procedure should be considered to allow better tissue perfusion and to reduce the risk of re-amputation.

Current status and progress in research on dressing management for diabetic foot ulcer.

Diabetic foot ulcer (DFU) is a major complication of diabetes and is associated with a high risk of lower limb amputation and mortality. During their lifetime, 19%-34% of patients with diabetes can develop DFU. It is estimated that 61% of DFU become infected and 15% of those with DFU require amputation. Furthermore, developing a DFU increases the risk of mortality by 50%-68% at 5 years, higher than some cancers. Current standard management of DFU includes surgical debridement, the use of topical dressings and wound decompression, vascular assessment, and glycemic control. Among these methods, local treatment with dressings builds a protective physical barrier, maintains a moist environment, and drains the exudate from DFU wounds. This review summarizes the development, pathophysiology, and healing mechanisms of DFU. The latest research progress and the main application of dressings in laboratory and clinical stage are also summarized. The dressings discussed in this review include traditional dressings (gauze, oil yarn, traditional Chinese medicine, and others), basic dressings (hydrogel, hydrocolloid, sponge, foam, film agents, and others), bacteriostatic dressings, composite dressings (collagen, nanomaterials, chitosan dressings, and others), bioactive dressings (scaffold dressings with stem cells, decellularized wound matrix, autologous platelet enrichment plasma, and others), and dressings that use modern technology (3D bioprinting, photothermal effects, bioelectric dressings, microneedle dressings, smart bandages, orthopedic prosthetics and regenerative medicine). The dressing management challenges and limitations are also summarized. The purpose of this review is to help readers understand the pathogenesis and healing mechanism of DFU, help physicians select dressings correctly, provide an updated overview of the potential of biomaterials and devices and their application in DFU management, and provide ideas for further exploration and development of dressings. Proper use of dressings can promote DFU healing, reduce the cost of treating DFU, and reduce patient pain.

Automatic Diabetic Foot Ulcer Recognition Using Multi-Level Thermographic Image Data.

Lower extremity diabetic foot ulcers (DFUs) are a severe consequence of diabetes mellitus (DM). It has been estimated that people with diabetes have a 15% to 25% lifetime risk of acquiring DFUs which leads to the risk of lower limb amputations up to 85% due to poor diagnosis and treatment. Diabetic foot develops planter ulcers where thermography is used to detect the changes in the planter temperature. In this study, publicly available thermographic image data including both control group and diabetic group patients are used. Thermograms at image level as well as patch level are utilized for DFU detection. For DFU recognition, several machine-learning-based classification approaches are employed with hand-crafted features. Moreover, a couple of convolutional neural network models including ResNet50 and DenseNet121 are evaluated for DFU recognition. Finally, a CNN-based custom-developed model is proposed for the recognition task. The results are produced using image-level data, patch-level data, and image-patch combination data. The proposed CNN-based model outperformed the utilized models as well as the state-of-the-art models in terms of the AUC and accuracy. Moreover, the recognition accuracy for both the machine-learning and deep-learning approaches was higher for the image-level thermogram data in comparison to the patch-level or combination of image-patch thermograms.

Neural network-based method to stratify people at risk for developing diabetic foot: A support system for health professionals.

Diabetes Mellitus (DM) is a chronic disease with a high worldwide prevalence. Diabetic foot is one of the DM complications and compromises health and quality of life, due to the risk of lower limb amputation. This work aimed to build a risk classification system for the evolution of diabetic foot, using Artificial Neural Networks (ANN). This methodological study used two databases, one for system design (training and validation) containing 250 participants with DM and another for testing, containing 141 participants. Each subject answered a questionnaire with 54 questions about foot care and sociodemographic information. Participants from both databases were classified by specialists as high or low risk for diabetic foot. Supervised ANN (multi-layer Perceptron-MLP) models were exploited and a smartphone app was built. The app returns a personalized report indicating self-care for each user. The System Usability Scale (SUS) was used for the usability evaluation. MLP models were built and, based on the principle of parsimony, the simplest model was chosen to be implemented in the application. The model achieved accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 85%, 76%, 91%, 89%, and 79%, respectively, for the test data. The app presented good usability (93.33 points on a scale from 0 to 100). The study showed that the proposed model has satisfactory performance and is simple, considering that it requires only 10 variables. This simplicity facilitates its use by health professionals and patients with diabetes.

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nation-wide cohort study

BackgroundNumerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use.MethodsA retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use.ResultsCurrent SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest.ConclusionSGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

ß-Lactamase and Antibiogram in Some Gram-Negative Bacteria Isolated from Foot Ulcer Patients

The foot infection is the most consequence of diabetes mellitus, which greatly increases the risk of lower limb amputation. Effective antibiotic therapy is crucial in the treatment of these illnesses. The gram-negative bacterial samples from individuals with diabetic foot infections are evaluated in this study for their pattern of antibiotic susceptibility. Eighty-foot ulcer patients in total were collected, and 115-gram negative bacteria were taken, identified, and confirmed for antibiotic sensitivity using several drugs from various families. Finally, the phenotypic detection of extended spectrum beta lactamase, AMPC, and metallo-beta-lactamase MBL was performed. The results found different types of gram-negative bacteria isolated which are E. coli, Pseudomonas spp., Klebsiella spp., and Proteus spp. Also, the results show the different percentages of resistance of these bacterial isolates to different types of antibiotics and also their different percentage in their sensitivity to different antibiotics. This research revealed that 50% of diabetic foot infections were caused by several microbes. The most often found gram-negative-bacteria were E coli, Pseudomonas spp., Klebsiella spp., and Proteus spp. These bacteria were recovered from the taken cases. on the other hand, our study found a noted percentage of different isolated gram-negative bacteria for producing three types of beta-lactamase enzymes.

Overcoming Barriers to Wound Healing in a Neuropathic and Neuro-Ischaemic Diabetic Foot Cohort Using a Novel Bilayer Biodegradable Synthetic Matrix.

Diabetes-related foot ulceration presents an increasing risk of lower limb amputation globally, driving the search for new treatment technologies. Our single-centre prospective observational study reports on the impact of bilayer biodegradable synthetic matrix technology (NovoSorb® BTM) on the healing and amputation rates of a diabetic foot ulceration cohort. Consecutive patients with a diabetes-related foot ulceration treated with NovoSorb BTM, between December 2019 and October 2021, were followed for 12 months. Complete wound healing and amputation outcomes were observed. Amputation risk was stratified using the Wound, Ischaemia and foot Infection (WIfI) classification system. Study outcomes were compared with recently published meta-analysis data to evaluate the impact of the synthetic matrix. In total, 25 NovoSorb BTM applications to 23 wounds in 22 patients were observed. Complete wound healing was observed in 15 of the wounds, 3 retained chronic wounds, 3 required minor amputation and 2 required major limb amputation. Further, 12-month WIfI amputation risk analysis saw 18 patients stratified to WIfI stage 4, 4 to WIfI stage 3 and 1 to WIfI stage 1. Our observed 12-month major amputation rates were 11.1% (n = 2) for stage 4 and 0% for stages 3 and 1. Our early experience suggests that NovoSorb BTM is a safe and effective treatment for moderate to severe diabetes-related foot ulceration. While larger-scale data are required, NovoSorb BTM may represent a promising new addition to the armamentarium of clinicians, who strive to achieve limb salvage in this complex cohort of patients.

Artificial Intelligence Based Prediction of Diabetic Foot Risk in Patients with Diabetes: A Literature Review

Diabetic foot is a prevalent chronic complication of diabetes and increases the risk of lower limb amputation, leading to both an economic and a major societal problem. By detecting the risk of developing diabetic foot sufficiently early, it can be prevented or at least postponed. Using artificial intelligence, delayed diagnosis can be prevented, leading to more intensive preventive treatment of patients. Based on a systematic literature review, we analyzed 14 articles that included the use of artificial intelligence to predict the risk of developing diabetic foot. The articles were highly heterogeneous in terms of data use and showed varying degrees of sensitivity, specificity, and accuracy. The most used machine learning techniques were support vector machine (SVM) (n = 6) and K-Nearest Neighbor (KNN) (n = 5). Future research is recommended on larger samples of participants using different techniques to determine the most effective one.

Risk of lower limb amputation in diabetic patients using SGLT2 inhibitors versus DPP4 inhibitors or GLP-1 agonists: a meta-analysis of 2 million patients.

The objective of this review was to assess the risk of lower limb amputation (LLA) in type 2 diabetic patients based on the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase 4 inhibitors (DPP4i) or glucagon-like peptide-1 receptor agonists (GLP1a). PubMed, CENTRAL, Scopus, Web of Science, and Embase were referenced for articles published up to 5 February 2023. All types of studies comparing the drugs for LLA risk and reporting hazard ratios (HR) were included. Thirteen studies with 2,095,033 patients were included. Meta-analysis of eight studies comparing SGLT2i with Dipeptidyl peptidase inhibitors (DPPi) showed that there was no difference in the risk of LLA between the two drug groups (HR: 0.98 95% CI: 0.73, 1.31 I2 = 89%). The outcomes were unchanged on sensitivity analysis. Another pooled analysis of six studies found no significant difference in the risk of LLA between SGLT2i and GLP1a users (HR: 1.26; 95% CI: 0.99, 1.60; I2 = 69%). The exclusion of a single study showed an increased risk of LLA with SGLT2i (HR: 1.35; 95% CI: 1.14, 1.60; I2 = 14%). The current updated meta-analysis found no significant difference in the risk of LLA between SGLT2i and DPP4i users. A tendency of increased risk of LLA was noted with SGLT2i as compared to GLP1a. Further studies shall increase the robustness of current findings.

Effect of SGLT2 inhibitors on the course of chronic heart failure in patients with type 2 diabetes mellitus

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, which is the result of impaired insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes is accompanied by damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Diabetes mellitus plays a significant role in the formation and is one of the significant risk factors for the development of chronic heart failure (CHF) through its glucose toxic effect, the effect on hyperlipidemia and blood coagulation, impaired autonomic regulation of the heart and a number of other mechanisms. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a recently emerging class of antidiabetic drugs that act by inhibiting the reabsorption of glucose in the kidneys. Existing studies of the efficacy and safety of these drugs have shown that they have not only antidiabetic, but also a pronounced organoprotective, especially cardioprotective effect. Today it is believed that the main reason leading to this lies in a decrease in sodium reabsorption in the kidneys, a decrease in the content of intracellular calcium and sodium, and an increase in the concentration of calcium in mitochondria. The role of the ketogenic action of these drugs, their effect on oxidative stress and the processes of inflammation and fibrosis in the myocardium is also considered. The most common side effects of SGLT2 inhibitors include urinary tract and genital infections, euglycemic ketoacidosis. Other possible side effects include an increased risk of lower limb amputations, Fournier gangrene, breast cancer in women, bladder cancer in men, orthostatic hypotension and acute kidney injury, and an increased tendency to fracture. Most side effects can be avoided through adequate patient education and assessment of risk factors and contraindications before starting the use of drugs. Despite the clear need for more research on SGLT2 inhibitors, their widespread use will positively affect the health of the diabetic patient population.

Clinical characteristics and risk factors of lower extremity amputation in patients with diabetic foot.

To investigate the risk factors of lower limb amputation, and help physicians better understand the clinical characteristics of patients with diabetic foot, and make treatment strategies for these patients correctly. In this study, the inpatients with diabetic foot treated in our hospital form January 2013 to February 2021 were reviewed retrospectively. The patients were divided into amputation and conservative treatment groups. The variables of the patients, consisting of age, gender, smoking history, alcohol use, diabetes and ulcer duration, ulcer size, Wagner classification, ankle brachial index, previous amputation history, laboratory data, and medical comorbidities including hypertension, coronary artery disease, peripheral arterial disease, chronic renal insufficiency, retinopathy, and sequelae of cerebral infarction were selected for analysis to determine the risk factors of lower limb amputation. In this study, a total of 856 patients with diabetic foot were enrolled, in which 487 patients received amputation surgeries, and the amputation rate was 56.9%. There were significant differences between the two groups in gender (p=0.014), smoking history (p=0.011), ulcer duration (p=0.023), ulcer size (p=0.000), Wagner classification (p=0.000), ABI (p=0.031), peripheral arterial disease (p=0.000), HDL-C (p=0.013), osteomyelitis (p=0.000), and fibrinogen (p=0.001). A stepwise multiple logistic regression analysis revealed that male gender (p=0.003), larger ulcer size (p=0.001), higher Wagner classification grades (p=0.002), higher rate of peripheral arterial disease (p=0.02) and osteomyelitis (p=0.0001), and increased fibrinogen level (p=0.004) were independent risk factors of lower limb amputation in patients with diabetic foot. The diabetic foot patients with male sex, larger ulcer size, higher grade of Wagner classification, peripheral arterial disease or higher fibrinogen level may face higher risk of lower limb amputation.

1079-P: Effectiveness and Safety of Empagliflozin in Routine Care: Results from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study

EMPRISE is a 5-year monitoring program that evaluates the effectiveness and safety of empagliflozin (EMPA) using Medicare and 2 U.S. commercial claims [2014-20 (2018 for Medicare) ]. We identified 190,226 patients ≥18 years with type 2 diabetes initiating EMPA or a dipeptidyl peptidase-4 inhibitors (DPP-4i) , and followed them up for heart failure hospitalization in primary (HHF-Specific) or any discharge positions (HHF-Broad) , a composite of myocardial infarction (MI) and stroke, and all-cause mortality (ACM) (Medicare only) . Safety outcomes were lower-limb amputations (LLA) , non-vertebral fractures, diabetic ketoacidosis (DKA) , acute kidney injury (AKI) , renal and bladder cancers (CA) . We estimated pooled HR (95% CI) after propensity score matching, adjusting for 143 baseline covariates. Compared to DPP4i, EMPA was associated with a reduced risk of HHF [HHF-Specific: 0.47 (0.41, 0.55) ; HHF-Broad: 0.67 (0.62, 0.72) ], a similar risk of the composite of MI or stroke [0.92 (0.84, 1.02) ], and a reduced risk of ACM [0.56 (0.46, 0.68) ]. EMPA was associated with a reduced risk of AKI [0.73 (0.68, 0.78) ], an increased risk of DKA [1.88 (1.51, 2.34) ], and a similar risk of LLA, fractures, and renal and bladder CA. Our findings support the cardiovascular effectiveness of EMPA in routine care with a safety profile in line with documented information. Disclosure P.T.Htoo: Employee; Johnson & Johnson. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; Boehringer Ingelheim International GmbH. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Microvascular disease increases the risk of lower limb amputation - A Western Danish cohort study.

Peripheral artery disease is the leading cause of nontraumatic lower limb amputation. Microvascular disease (MVD) increases the risk of lower limb amputation in patients with peripheral artery disease (PAD). We estimated the risk of lower limb amputation associated with MVD and PAD in a Danish cohort. We included every resident without previous lower limb amputation in Western Denmark aged 50-75 years on 1 January 2012 and followed them for 7 years. Participants were stratified by MVD and PAD. We estimated adjusted hazard ratios of lower limb amputation using individuals with no MVD and no PAD as reference. We also provide a sex-specific analysis and estimated the population attributable fraction of the male sex. We included 933,597 individuals, of whom 16,741 had MVD only, 18,217 had PAD only and 1,827 had MVD and PAD. Both MVD only (adjusted hazard ratio 3.36, 95% CI 2.98-3.73) and PAD only (adjusted hazard ratio 7.32, 95% CI 6.62-8.08) increased the risk of lower limb amputation separately. Individuals with MVD and PAD had the highest risk of amputation (adjusted hazard ratio 12.27, 95% CI 10.43-14.80). Men had an increased absolute risk of amputation. The population attributable fraction associated with the male sex was 31%. Microvascular disease and PAD are independently associated with a threefold and sevenfold increase of amputation risk, respectively. Combined, they had an additive effect constituting a 12-fold amputation risk. The amputation risk was higher in men than women, and 3 in 10 amputations were attributed to the male sex.

Nationwide Trends in Dispensing of Sodium Glucose Cotransporter 2 Inhibitors.

Three large cardiovascular outcome trials have investigated the safety of sodium glucose cotransporter 2 (SGLT2) inhibitors. To analyze the nationwide dispensing of SGLT2 inhibitors before and after the publication of these trials. A cross-sectional study was conducted of monthly prescription dispensing of SGLT2 inhibitors from May 23, 2014, to April 30, 2019, using nationwide data for Canada. An autoregressive integrated moving average (ARIMA) model was fitted to the monthly number of tablets dispensed for each SGLT2 inhibitor; the model included a ramp intervention function at the publication dates of interest to estimate the impact on SGLT2 inhibitor dispensing patterns. The rate of canagliflozin and dapagliflozin dispensing declined after publication of results of the empagliflozin cardiovascular trial in September 2015. After publication of results of the canagliflozin trial in June 2017, which indicated a reduction in cardiovascular events and an increase in the risk of lower-limb amputation, canagliflozin remained the most commonly dispensed SGLT2 inhibitor, but its rate of dispensing declined further. In contrast, the rate of empagliflozin dispensing increased, while the rate of dapagliflozin dispensing was unchanged. After publication of the dapagliflozin trial in November 2018, which indicated no clear reduction in cardiovascular events, short-term trends in dispensing of canagliflozin, empagliflozin, and dapagliflozin were largely unaffected. The cardiovascular outcome trials appeared to have an important impact on the dispensing of SGLT2 inhibitors in Canada.

Lower limb amputations: protection with GLP-1 receptor agonists rather than increased risk with SGLT2 inhibitors?

An increased risk of lower limb amputations (LLA) has been suspected with the use of sodium-glucose cotransporter type 2 inhibitors (SGLT2is) after the publication of CANVAS with canagliflozin compared with placebo. A more than twofold increase of the risk of LLA in SGLT2i users compared with patients treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been reported in a Scandinavian cohort observational study, yet other observational studies gave less alarming findings. Our meta-analysis of 12 retrospective cohorts revealed significant increase in LLA with a HR 1.15 (95% CI 1.05-1.24, I² 69%) when comparing SGLT2i users versus GLP-1RA users. However, another meta-analysis of observational studies showed no increased risk when SGLT2is were compared to dipeptidyl peptidase-4 inhibitors (DPP-4is) and some data showed a lower incidence of LLA in patients treated with GLP-1RAs compared to those treated with DPP-4is. When summarizing all available data with direct and indirect comparisons, a conclusion emerges that SGLT2is do not increase the risk of LLA but rather that GLP-1RAs may reduce such a risk.

Association Between the ACE Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes.

The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes. ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below-the-ankle amputation consisting of at least one ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic, and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] vs. II) and plasma ACE, after adjusting for confounders. Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03-4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 1.16-13.67]). This association was driven by excess risk of minor, but not major, LLA. The D allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33-4.65]). LLA was associated with higher mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers. This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes.